ACTION (AT1R and CCR2 TARGETS FOR INFLAMMATORY NEPHROSIS) PHASE 2 TRIAL FOR DIABETIC KIDNEY DISEASE

S ROGER1, D PACKHAM2,3,  R SHEPHERD2, H HEERSPINK4
1Gosford Hospital, Gosford, Australia, 2Dimerix Limited, Melbourne, Australia, 3Melbourne Renal Research Group, Reservoir, Australia, 4University Medical Center, Groningen, Netherlands

Aim: To determine the effect of dual inhibition of angiotensin II receptor type 1 (AT1R) chemokine receptor 2 (CCR2) in diabetic kidney disease (DKD).
Background: The mechanism of disease progression in DKD is multifactorial and involves hyperfiltration, inflammation and podocyte damage. The AT1R antagonist irbesartan is the only therapy registered in Australia for prevention of disease progression. CCR2 has also been implicated in DKD pathogenesis, and AT1R and CCR2 are G protein coupled receptors known to act both as monomers and functional heteromers. This heteromerisation enables bypass of single receptor blockade. Subgroup analysis of n=10 patients with DKD in a previous Phase 2a study of patients treated with simultaneous blockade of both AT1R with irbesartan and CCR2 with propagermanium, a receptor antagonist registered for the treatment for hepatitis B in Japan, showed a clinically and statistically significant reduction in 24-hr albumin/creatinine (uACR) of 35.6% from baseline (p=0.0019) after 26-weeks treatment.
Methods: A multi-centre, randomised, placebo-controlled, two-way crossover study in 40 DKD patients is planned. Patients will receive irbesartan 300mg/day for at least 3 months prior to and throughout the study. The safety profile and reduction in albuminuria from baseline will be determined following treatment with propagermanium or placebo for a period of 12-weeks, followed by a 6-week washout period, and a further 12-week period of treatment with placebo or propagermanium. Key inclusion criteria include a screening urine albumin/creatinine ratio between 30-500 mg/mmol and an eGFR between 25-90 ml/min/1.73m2.
Conclusions: Although the progression of DKD has slowed over the past 20 years with AT1R antagonists and now SGLT-2 inhibitors, new combination therapy may offer even greater benefits by addressing the multiple mechanisms of disease progression.


Biography:
Simon Roger underwent advanced training in Nephrology at Westmead Hospital, followed by two years of clinical and laboratory research in London. In 1993, Dr Roger was appointed as a nephrologist to Royal North Shore Hospital, and that year, took over as Medical Head of the Division of Medicine at Gosford Hospital. He is a past Chairman of the Gosford Hospital Medical Staff Council. In 2000 he was appointed Clinical Associate Professor at the University of Newcastle and in 2012 he was selected as the inaugural Conjoint Professor of Medicine within his Local Hospital District and the University.

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